The purpose of this research project is to determine mechanisms responsible for altered glucose uptake, metabolism, and transport by the growth restricted placenta. These studies are important for defining physiological and biochemical mechanisms responsible for placental dysfunction in the IUGR placenta, as placental insufficiency is responsible for most cases of human IUGR. The nature and mechanisms of these functional deficiencies have not been determined, yet they are fundamental to understanding how the placenta directly affects fetal growth and development. First, we will more completely determine and understand the physiological mechanisms responsible for decreased placental glucose transport capacity and metabolism in the IUGR placenta. Second, we will determine whether changes in GLUT 1 and/or 3 expression are responsible for decreased placental glucose uptake, transport capacity, and metabolism in the IUGR placenta. Third, we will determine whether experimental increases in fetal and/or maternal plasma glucose, insulin, or IGF-I concentrations will increase expression of Glut 1 and/or Glut 3 in trophoblast membranes in the IUGR placenta and normalize glucose transport capacity, thus defining whether deficient glucose transport in the IUGR placenta can be improved by maternal or fetal nutrient and hormone treatments. Experimental approaches include: 1) our established, natural model of placental insufficiency and IUGR in pregnant sheep produced by chronic exposure of the pregnant ewe to a hyperthermic environment; 2) our established but unique Fick principle and radioactive and stable isotopic tracer techniques; 3) established and novel cell and molecular techniques to quantify and localize placental glucose transporters in relation to glucose transport and metabolic kinetics in a variety of trophoblast cells; 4) our established acute and chronic intravenous clamps of glucose, insulin, and IGF-I to determine kinetics of placental glucose uptake, metabolism, and transport rates. These are essential studies to conduct, as IUGR, primarily caused by placental insufficiency, is an important national and international health problem affecting the fetus, neonate, child, and adult.